Substituted 10-ethynyldibenzo[b,f]thiepins and dibenz[b,f]oxepins

ABSTRACT

Compounds of the formulas    &lt;IMAGE&gt;  I   &lt;IMAGE&gt; Ia WHEREIN R1, R2, R3, R4, R5, R6, R7, R8 and X are as hereinafter set forth, ARE DESCRIBED. The compounds of formulas I and Ia are useful as neuroleptic agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a division, of application Ser. No. 500,770 filed Aug. 26, 1974,now U.S. Pat. No. 3,928,383, issued Dec. 23, 1975, which in turn is acontinuation-in-part of Ser. No. 380,653, filed July 12, 1973, nowabandoned.

BRIEF SUMMARY OF THE INVENTION

The invention relates to compounds of the formulas ##STR2## WHEREIN X isoxygen or sulfur; R₁ and R₂, independently, are hydrogen or lower alkyl;R₃ is hydrogen; R₄ and R₅, independently, are hydrogen, lower alkyl,hydroxy-lower alkyl, alkanoyloxy-lower alkyl or, when taken together,are a saturated 5-or 6-membered heterocyclic ring, which may contain anoxygen, a sulfur or an additional nitrogen atom, and which may besubstituted by lower alkyl, hydroxy-lower alkyl or alkanoyloxy-loweralkyl; R₆ is lower alkyl, lower alkyl-sulfonyl, hydroxy, lower alkoxy,lower alkythio, di-(lower alkyl)-sulfamoyl, halogen, trifluoromethyl,nitro, amino or di-(lower alkyl)amino; and R₇ and R₈ ; independently,are hydrogen, lower alkyl, lower alkoxy, lower alkyl-sulfonyl, hydroxy,lower alkylthio, di-(lower alkyl)-sulfamoyl, halogen, trifluoromethyl,nitro, amino or di-(lower alkyl)-amino,

and the corresponding N-oxides and the pharmaceutically acceptable acidaddition salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to compounds of the formulas ##STR3## wherein X isoxygen or sulfur; R₁ and R₂, independently, are hydrogen or lower alkyl;R₃ is hydrogen; R₄ and R₅, independently, are hydrogen, lower alkyl,hydroxy-lower alkyl, alkanoyloxy-lower lower alkyl or, when takentogether, are a saturated 5- or 6- membered heterocyclic ring, which maycontain an oxygen, a sulfur or an additional nitrogen atom, and whichmay be substituted by lower alkyl, hydroxy-lower alkyl oralkanoyloxy-lower alkyl; R₆ is lower alkyl, lower alkyl-sulfonyl,hydroxy, lower alkoxy, lower alkylthio, di-(lower alkyl)-sulfamoyl,halogen, trifluoromethyl, nitro, amino or di-(lower alkyl)-amino; and R₇and R₈, independently, are hydrogen, lower alkyl, lower alkoxy, loweralkyl-sulfonyl, hydroxy, lower alkylthio, di-(lower alkyl)-sulfamoyl,halogen, trifluoromethyl, nitro, amino or di-(lower alkyl)-amino,

and the corresponding N-oxides and the pharmaceutically acceptable acidaddition salts thereof.

As used herein, the term "lower alkyl" denotes a straight chain orbranched chain hydrocarbon of 1-7 carbon atoms, for example, methyl,ethyl, propyl, butyl, and the like. The term "lower alkoxy" denotes alower alkyl ether group in which the lower alkyl moiety is as definedabove, for example, methoxy, ethoxy, propoxy, butoxy, and the like. Theterm "lower alkylthio" denotes a lower alkylthio ether group in whichthe lower alkyl moiety is as defined above, for example, methylthio,ethylthio, propylthio, butylthio, and the like. The term alkanoyloxydenotes a straight or branched chain lower alkanoyloxy group of 2-18carbon atoms, preferably of 2-10 carbon atoms, for example, acetoxy,pivaloyloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy, octanoyloxy,nonanoyloxy, decanoyloxy, tetradecanoyloxy, hexadecanoyloxy,octadecanoyloxy, and the like. The 5- or 6-membered heterocyclic ringswhich may contain two nitrogen atoms, or one nitrogen atom, or onenitrogen atom and an oxygen or sulfur atom are exemplified bypyrrolidino, piperazino, piperidino, morpholino, thiomorpholino,methylpiperidino, and the like. The lower alkyl, hydroxy-lower alkyl, oralkanoyloxy-lower alkyl which may be substituted on the heterocyclicmoiety is preferably connected to the second nitrogen of the piperazinemoiety; exemplary of such are N-methylpiperazino,N-hydroxyethylpiperazino, N-hydroxypropylpiperazino,N-heptanoyloxypropylpiperazino. All the halogens are included, i.e.,fluoro, chloro, bromo and iodo. Chloro is preferred.

It has been discovered that the compounds of formulas I and Ia of theinvention, their N-oxides and pharmaceutically acceptable salts thereof,demonstrate strong neuroleptic activity. They can, therefore, beutilized for the treatment of, for example, acute or chronicschizophrenia, as well as tranquilizers. Advantageously, the compoundsof the invention demonstrate no or only very weak cataleptic sideeffects, so that no or only insignificant motor disturbances areobserved. The compounds of formula Ia are preferred. Preferred compoundsof formulas I and Ia of the invention are those wherein R₁ is hydrogen.

A preferred subgenus also comprises the compounds of formulas I and Iawherein X is sulfur. Yet another preferred group of the compounds of theinvention are those of formulas I and Ia wherein R₄ and R₅ are loweralkyl, especially methyl.

Still another preferred subgenus comprises the compounds of formulas Iand Ia of the invention, wherein R₆ is methylthio or chloro and R₇ andR₈ are hydrogen. Yet again, those derivatives wherein R₆ is chloro, R₇is hydrogen and R₈ is methoxy are also preferred. An especiallypreferred group of the compounds of formula Ia of the inventioncomprises those wherein R₁ is hydrogen, R₄ is hydrogen or lower alkyl,R₅ is lower alkyl, hydroxy-(lower alkyl) or alkanoyloxy-(lower alkyl),or R₄ and R₅, taken together with the nitrogen atom to which they areattached are a saturated 5-membered or 6-membered heterocyclic ringwhich may contain oxygen or an additional nitrogen and which may besubstituted by hydroxy-(lower alkyl) or alkanoyloxy-(lower alkyl), R₆ ishalo or lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl,di-(lower alkyl)-sulfamoyl, trifluoromethyl, nitro, amino or di-(loweralkyl)-amino, and one of R₇ and R₈ is hydrogen and the other is halo,lower alkyl or lower alkoxy. Preferred within this last-mentioned groupof compounds are those wherein R₁ is hydrogen, R₄ is hydrogen, methyl orethyl, R₅ is methyl, ethyl, hydroxyethyl or acetoxyethyl or R₄ and R₅,taken together with the nitrogen atom to which they are attached arepiperidino, pyrrolidino, morpholino, N-hydroxyethylpiperazino orN-acetoxyethylpiperazino, R₆ is chloro, methyl, methoxy, methylthio,methylsulfonyl, dimethylsulfamoyl, trifluoromethyl, nitro, amino ordimethylamino, R₇ is hydrogen, chloro or methyl and R₈ is hydrogen,methyl or methoxy. Particularly preferred compounds of the invention areN,N-dimethyl-3-[8-(methylthio)-dibenzo[b,f]thiepin-10-yl]-2-propynylamine,N,N-dimethyl-3-(8-chlorodibenzo[b,f]thiepin-10-yl)-2-propynylamine andN,N-dimethyl-3-(8-chlorodibenzo[b,f]thiepin-10-yl)-2-propynylamine andN,N-dimethyl-3-(8-chloro-3-methoxy-dibenzo[b,f]thiepin-10-yl)-2-propynylamine,or the pharmaceutically acceptable addition salts thereof.

Th tricyclic compounds of formulas I and Ia, as well as their N-oxidesand pharmaceutically acceptable salts thereof, can be prepared throughprocesses as hereinafter described: ##STR4## wherein R₁, R₂, R₃, R₆, R₇,R₈ and X are as hereinbefore described, except that a hydroxy group canalso be protected, respectively, is reacted with formaldehyde and acompound of the formula ##STR5## wherein R₄ and R₅ are as hereinbeforedescribed, or

b. A compound of the formula ##STR6## wherein R₁, R₂, R₃, R₆, R₇, R₈ andX are as hereinbefore described, and Y is a leaving group, except that ahydroxy group can also be protected,

respectively, is reacted with a compound of the formula ##STR7## whereinR₄ and R₅ are as hereinbefore described, or

c. For the preparation of a compound of formula Ia, a compound of theformula ##STR8## wherein R₁, R₄, R₅, R₆, R₇, R₈ and X are ashereinbefore described, except that a hydroxy group can also beprotected, is dehydrated, or

d. For the preparation of a compound of formula I or Ia, wherein R₄ ishydrogen or lower alkyl and R₅ is lower alkyl, a compound of the formula##STR9## wherein R₁, R₂, R₃, R₆, R₇, R₈ and X are as hereinbeforedescribed, and R'₄ is hydrogen or lower alkyl, except that a hydroxygroup can also be protected, respectively, is alkylated, or

e. For the preparation of an N-oxide of a compound of formula I or Iawherein R₄ and R₅ is other than hydrogen, a compound of the formula##STR10## wherein R₁, R₂, R₃, R₆, R₇, R₈ and X are as hereinbeforedescribed; R"₄ and R"₅ are lower alkyl, hydroxy-(lower alkyl)- oralkanoyloxy-(lower alkyl), or R"₄ and R"₅, taken together with thenitrogen atom, are a saturated 5-membered or 6-membered heterocyclicring which may contain oxygen, sulfur or an additional nitrogen andwhich may be substituted by lower alkyl, hydroxy-(lower alkyl)-, oralkanoyloxy-(lower alkyl)-, respectively, is oxidized; or

f. For the preparation of a compound of formula I or Ia wherein R₄ ishydrogen and R₅ is alkanoyloxy-(lower alkyl), a compound of the formula##STR11## wherein R₁, R₂, R₃, R₆, R₇, R₈ and X are as hereinbeforedescribed, R₅ '" is hydroxy-(lower alkyl)- except that any hydroxy groupdefined by R₆, R₇ and R₈ can also be protected, is reacted with analkanoylating agent, or

g. Convert a base of formula I or Ia or an N-oxide thereof into thecorresponding pharmaceutically acceptable acid addition salt.

The compounds of formulas II, IIa, IV, IVa, V, Va, VI, VIa, VII, VIIa,VIII and VIIIa are novel and also within the scope of the invention.

The following description will further illustrate the processes for thepreparation of the tricyclic compounds of the invention, as well astheir salts and respectively, their pharmaceutically acceptable acidaddition salts.

The starting materials of formula IIa can be prepared by the reaction ofthe corresponding 10-ketones with an acetylene/metal organic compound,for example, lithium acetylide, an acetylene-magnesium halide ortrimethylsilylethynyl lithium. The lithium acetylide is preferablyreacted in liquid ammonia and/or an organic solvent, for example,tetrahydrofuran or benzene, or as a complex with ethylene diamine in aninert organic solvent, such as dioxane, tetrahydrofuran or benzene at atemperature between about -10° C. and the boiling point of the reactionmixture. The acetylene/magnesium halide and the trimethylsilylethynyllithium are preferably reacted in an organic solvent such astetrahydrofuran or benzene, at a temperature between about -10° C. andthe boiling point of the reaction mixture. The resulting additionproduct is subsequently hydrolyzed, for example, by reacting withaqueous ammonium chloride solution at room temperature. The resulting10-ethynyl-10-carbinol or, when trimethylsilylethynyl lithium is used,the resulting 10-trimethylsilylethynyl-10-carbinol, is subsequentlydehydrated, for example, by heating with a strong acid such asp-toluenesulfonic acid in an organic solvent such as methylene chloride,carbon tetrachloride, acetonitrile, benzene, o-, m- or p-xylene, wherebythere is obtained the compound of formula IIa or, whentrimethylsilylethynyl lithium is used, the corresponding10-trimethylsilylethynyl compounds. These latter compounds are subjectedto a metal-catalyzed hydrolysis by, for example, treatment in aqueousacetone or in aqueous ethanol with silver nitrate and potassium cyanide.The trimethylsilyl group is cleaved under these conditions, even at roomtemperature, and there is obtained a starting material of formula IIa.

The compounds of formula II can be prepared, for example, by thereaction of the corresponding tricyclic 10-halo compound, for example,the chloro compound, with an acetylene/metallic organic compound asdescribed above. The reaction, preferably is carried out in an inertorganic solvent such as, for example, ether, benzene or tetrahydrofuran,at a temperature between about -10° C. and the boiling point of thereaction mixture.

The preparation of the compounds of the invention from the startingmaterials of formulas II and IIa by reaction with formaldehyde and acompound of formula III in accordance with embodiment (a) is carried outin accordance with a Mannich reaction. Preferably, it is carried out inthe presence of an inert organic solvent, for example, in the presenceof a lower alkanol such as methanol or ethanol, a cyclic ether, forexample, dioxane, or a lower alkanecarboxylic acid such as acetic acid;alternatively, in admixture with water. The temperature of the reactionis in the range of from about 0° to 100°. The reaction is preferablycatalyzed by metal salts, especially copper (II) salts such as copper(II) acetate.

The symbol Y of the starting materials of formula IV or IV preferably ishalogen or alkyl-substituted or aryl-substituted sulfonyloxy.Preferably, the substituent on the sulfonyl moiety is alkyl or aryl suchas lower alkyl, especially methyl or phenyl or p-tolyl. Y as halogen ispreferably chloro or bromo.

The 10,11-unsaturated compounds of formula IVa can be prepared, forexample, by reacting the corresponding tricyclic 10-ketones, which areknown compounds or can be prepared according to known procedures, with ametallo organic compound of 2-propynyl-2-tetrahydropyranyl ether, forexample, with the corresponding lithium or magnesium halide compound.The metallo organic compound of 2-propynyl-2-tetrahydropyranyl ethercarries the corresponding metal radical, for example, lithium ormagnesium halide radical on the carbon in the 3-position of the2-propynyl moiety. The lithium compound is preferably reacted in liquidammonia and/or an organic solvent, such as, for example,tetrahydrofuran, the magnesium halide compound is reacted in an organicsolvent such as tetrahydrofuran, at a temperature between about -10° Cand the boiling point of the reaction mixture. The resulting additioncompound is subsequently subjected to hydrolysis, for example, bytreatment with aqueous ammonium chloride at room temperature, and theresulting tricyclic10-[3-(2-tetrahydropyranyloxy)-1-propynyl]-10-carbinol is subjected todehydration/hydrolysis, for example, by treatment with a strong acidsuch as p-toluenesulfonic acid, in methylene chloride, benzene or o-, m-or p-xylene at the boiling temperature of the reaction mixture, andsubsequently, boiling with p-toluenesulfonic acid in aqueous ethanol,the dehydration product being thus hydrolyzed. The resulting10,11-unsaturated, tricyclic 10-(3-hydroxy-1-propynyl) compound can nowbe converted to the corresponding 10,11-unsaturated reactive ester offormula IVa, for example, by reaction with the correspondingalkyl-substituted or aryl-substituted sulfonic acid halide, for example,the chloride, or with thionyl chloride or thionyl bromide. Anothermethod for the preparation of the 10,11-unsaturated starting materialsof formula IVa is described in Example 5 hereinafter.

The 10,11-saturated compound of formula IV can be prepared by reactingthe corresponding tricyclic 10-halo compound, for example, the chlorocompound, which are known compounds or can be prepared according toknown procedures, with one of the above-mentioned metallo organiccompounds of 2-propynyl-2-tetrahydropyranyl ether. The resulting10,11-saturated, tricyclic10-[3-(2-tetrahydro-pyranyloxy)-1-propynyl]compound can subsequently, asdescribed above, be hydrolyzed and the corresponding 10,11-saturatedreactive ester of formula IV prepared.

The reaction in accordance with the invention of a compound of formulaIV or IVa and a compound of formula III can be carried out in an inertorganic solvent such as benzene, toluene, dimethylformamide, or thelike. Preferably, the reaction is carried out in the presence of anexcess of the compound of formula III, whereby it also serves as anacid-binding agent. As other acid-binding agents in this reaction, therecan be utilized, for example, anhydrous potassium carbonate. Whenemploying a readily volatile compound of formula III, the reaction issuitably carried out in a sealed vessel at elevated temperatures, forexample, at a temperature in the range of from about 50° to about 175°.The reaction temperature is not critical. Expediently, it is in therange of from about -20°C. to about the boiling point of the reactionmixture; preferably, between room temperature and the boiling point ofthe reaction mixture.

The tricyclic 10-carbinols of formula V can be prepared, for example, bythe reaction of the corresponding tricyclic 10-ketones, which are knowncompounds or can be prepared according to known procedures, with ametallo organic compound of the correspondingly substituted2-propynylamine which may be N-substituted. For example, there can bereacted the corresponding lithium or magnesium halide compound; themetal radical is in the 3-position of the 2-propynylamine. Lithiumcompounds are preferably reacted in liquid ammonia and an organicsolvent such as tetrahydrofuran; magnesium halogen compounds are reactedin an organic solvent such as tetrahydrofuran, at the boiling point ofthe reaction mixture. The resulting addition compound is subsequentlysubjected to hydrolysis, for example, by treatment with aqueous ammoniumchloride at room temperature, whereby the corresponding tricycliccarbinol of formula V is obtained.

The 11-carbinols of formula V can be prepared, for example, by thereaction of a tricyclic 10,11-epoxide, which are known compounds or canbe prepared according to known procedures, with the above-describedmetallo organic compound of the correspondingly substituted2-propynylamine. The lithium compound is preferably reacted in liquidammonia and an organic solvent such as tetrahydrofuran; the magnesiumhalide is preferably reacted in an organic solvent such astetrahydrofuran at the boiling point of the reaction mixture. Thismethod is particularly well suited for the preparation of symmetricallysubstituted starting materials of formula V, for example, the2,8-dichloro or the 2,8-dimethyl compounds. The utilization ofunsymmetrically substituted 10,11-epoxides results in a mixture ofsteroisomers, for example, in a mixture of 2-substituted and8-substituted compounds which can be separated according to knownmethods, for example, by column chromatography.

The dehydration of the starting materials of formula V in accordancewith embodiment (c) of the invention leads to the 10,11-unsaturatedcompounds of formula Ia. The dehydration can be carried out suitably byutilizing a strong acid, for example, an organic sulfonic acid, such asp-toluenesulfonic acid, methane-sulfonic acid or a mineral acid such ashydrochloric or hydrobromic acid, in an aqueous or non-aqueous medium.Preferably, the dehydration is carried out in an organic sulfonic acid,for example, p-toluenesulfonic acid, in the presence of an inert organicsolvent, such as methylene chloride, carbon tetrachloride, acetonitrile,benzene or o-, m- or p-xylene. When utilizing a mineral acid, this iscarried out, for example, in solution in a lower alkanol. Thedehydration can also be carried out by heating in a high-boilingnon-aqueous solvent such as dimethylsulfoxide. Other known dehydratingagents can likewise be utilized, for example, acetic anhydride. Thetemperature for the dehydration preferably is in the range of from about50° to about 200°.

For the alkylation of the compounds of formula Vi or formula Via inaccordance with embodiment (d) of the process of the invention, severalmethods are available.

In case a tertiary amine of formula I or Ia is desired, it can beprepared, for example, as follows:

A starting material of formula VI or VIa, respectively, is reacted witha compound of the formula

    R'.sub.5 Y.sub.1

wherein R'₅ is lower alkyl and Y₁ is a leaving group, for example,halogen such as chlorine, bromine or iodine or lower alkanesulfonyloxy,benzenesulfonyloxy or lower alkylbenzenesulfonyloxy.

As the alkylating agent, there can also be used ethylene oxide, whichmay be substituted by lower alkyl and in this manner, there isintroduced hydroxyethyl which may be substituted by lower alkyl. Thereaction preferably is carried out in an inert solvent, for example, alower alkanol such as ethanol, or dimethylformamide, at a temperature inthe range of from about 15° to about 75°.

In another process for the preparation of the tertiary amines of formulaI or Ia, a starting material of formula VI or VIa, respectively, isreacted with a mixture of formaldehyde and formic acid, preferably in anexcess at an elevated temperature, for example, at a temperature in therange of from about 50° to about the boiling point of the reactionmixture. Instead of formic acid, sodium borohydride can be utilized inthis reaction.

The starting materials of formulas VI and VIa, wherein R'₄ is hydrogen,that is, primary amines of formula VI or VIa, can be converted intosecondary amines of formula I or Ia by reacting a primary amine offormula VI or VIa, respectively, with a haloformic acid ester, forexample, chloroformic or bromoformic acid ethyl ester, to form acarbamate; the carbamate is subsequently reduced with a complex metalhydride, for example, lithium aluminum hydride. Both reaction steps arepreferably carried out in an inert solvent, for example, in ether ortetrahydrofuran, at a temperature in the range of from about roomtemperature to the reflux temperature of the reaction mixture,especially at the reflux temperature.

In another process for preparing the secondary amines of formula I orIa, a primary amine of formula VI or VIa, respectively, is reacted withchloral, preferable in an inert solvent such as chloroform or benzene,at an elevated temperature, for example, at a temperature in the rangeof between about 50° and the boiling point of the reaction mixture. Theresulting formylamino compound is subsequently reduced with a complexmetal hydride, for example, lithium aluminum hydride, in anhydrous etherto a secondary amine corresponding to formula I or Ia.

In another method for preparing the secondary amines of formula I or Ia,a primary amine of formula VI or VIa, respectively, is reacted withformaldehyde, preferably in an inert solvent, for example, benzene ortoluene, at a temperature in the range of from about room temperatureand the boiling point of the reaction mixture. The resulting Schiff'sbase is subsequently converted to a secondary amine of formula I or Iareduction. The reduction is suitably carried out by treatment of theSchiff's base with a complex metal hydride such as sodium borohydride orlithium aluminum hydride in anhydrous ether or dioxane.

The oxidation, according to embodiment e) of the process aspects of theinvention, of a compound of formula VII or VIIa results in thecorresponding N-oxide. As the oxidizing agent, preferably hydrogenperoxide or an organic peracid, for example, m-chloroperbenzoic acid, isused. Advantageously, the oxidation is carried out in an inert organicsolvent, for example, in a lower alkanol such as methanol or ethanol,ether, benzene, chloroform or methylene chloride, at a temperature inthe range of from about -50° C. to about room temperature, preferably ata temperature between about 0° C. and room temperature. After removal ofthe excess oxidizing agent and work-up according to known procedures,there is obtained the corresponding N-oxide. The latter can then beconverted, conveniently, into a pharmaceutically acceptable acidaddition salt.

The alkanoylation of a compound of formula VIII or VIIIa in accordancewith embodiment f) of the process aspects of the invention can becarried out conveniently by heating at a temperature in the range offrom about 50° to about 150° with a reactive derivative of thecorresponding alkanecarboxylic acid, for example, the corresponding acidchloride or acid anhydride. The esterification can also be carried outby reaction with an alkanecarboxylic acid in the presence of a strongacid catalyst, for example, sulfuric acid or p-toluenesulfonic acid, orin the presence of of a dehydrating agent, for example,dicyclohexylcarbodiimide or carbonyldiimidazole. The esterification ispreferably carried out in an organic solvent, for example, benzene,toluene or pyridine.

If it is desired to prepare a compound of formula I or Ia, wherein R₆and, if desired, R₇ and/or R₈, is hydroxy, or a corresponding N-oxide,there is preferably used a starting material of formula II, IIa, V, Va,VI, VIa, VII, VIIa, VIII or VIIIa, respectively, in which the hydroxygroup is protected, for example, by a lower alkyl, benzyl ortrimethylsilyl group. After completion of any desired reaction, theprotecting group is cleaved. An alkyl group is preferably cleaved bytreatment with a pyridine salt, for example, pyridine hydrochloride, ifnecessary in the presence of water, or by treatment with a borontrihalide, for example, boron tribromide or boron trichloride; a benzylgroup is preferably cleaved in a manner similar to that described forthe cleavage of a lower alkyl group or by treatment with an alkalimetal, such as sodium, in a lower alkanol, such as butanol; and atrimethylsilyl group is preferably cleaved by acid-catalyzed hydroysis,for example, by treatment with aqueous-alcoholic mineral acid such asaqueous ethanolic hydrochloric acid. The cleavage is preferably carriedout in an inert organic solvent, for example, benzene, toluene, xylene,or a halogenated hydrocarbon, such as methylene chloride, chloroform orcarbon tetrachloride, at a temperature in the range of from about roomtemperature to about the boiling point of the mixture, except that whena boron trihalide is utilized in the cleavage reaction, the temperatureconveniently is in the range of from about -70° C. to about roomtemperature.

The obtained bases of formulas I and Ia form salts with inorganic aswell as organic acids, for example, with hydrohalic acids such ashydrochloric acid, hydrobromic acid or hydroiodic acid, with othermineral acids such as sulfuric acid, phosphoric acid or nitric acid;also with organic acids such as tartaric and acetic acid, citric acid,camphorsulfonic acid, methanesulfonic acid, toluenesulfonic acid,ascorbic acid, maleic acid, mandelic acid and the like. Preferred saltsare those formed with hydrohalic acid. Especially preferred are thoseformed with hydrochloric acid and maleic acid. The pharmaceuticallyacceptable acid addition salts, preferably, can be prepared in an inertsolvent, for example, ethanol, acetone, acetonitrile, by treating thefree base with the corresponding anhydrous acid.

The bases of formulas I and Ia are partly crystalline, solid substanceswhich are relatively soluble in dimethylsulfoxide, dimethylformamide, orin chlorinated hydrocarbons such as chloroform, methylene chloride, orin a alkanol such as methanol or ethanol, and are relatively insolublein water.

The pharmaceutically acceptable acid addition salts of the bases offormulas I and Ia are crystalline, solid substances. They are freelysoluble in dimethylsulfoxide and dimethylformamide, in an alkanol suchas methanol or ethanol, and also in chloroform, methylene chloride andwater. The pharmaceutically acceptable addition salts of the bases offormulas I and Ia are relatively insoluble in benzene, ether andpetroleum ether.

The compounds of formulas I and Ia are useful as neuroleptic agents,substantailly devoid of cataleptic activity or effect.

A cataleptic effect (wax-like rigidity, that is, maintaining for anabnormally long period a forced upon body position) is considered to bea disturbing side effect with neuroleptically active compounds andindicates motor disturbances. The products according to the inventionhave the advantage that they do not have this disturbing side effect orhave it only to a very slight extent. To prove the lack of catalepticactivity, representative samples of the end products of the inventionwere administered intraperitoneally to rats. The following compoundswere tested:

Product A:N,N-dimethyl-3-[8-(methylthio)-dibenzo[b,f]thiepin-10-yl]-2-propynylaminemaleate;

Product B:N,N-dimethyl-3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propynylaminemaleate;

Product C:N,N-dimethyl-3-(8-chloro-3-methoxydibenzo[b,f]thiepin-10-yl)-2-propynylaminemethanesulfonate.

The foregoing compounds were compared to chlorpromazine, a well-knowncentral depressant, especially well-known as a neuroleptic agent. Thetest animals are considered to be cataleptic when the homolateralextremities remain in the crossed position for at least 10 seconds. Thenumber of cataleptic animals is recorded every 30 minutes over a 6-hourperiod. The ED₅₀ is the dose at which 50% of the animals are cataleptic.

    __________________________________________________________________________    RESULTS:                                                                      Test Substance              ED.sub.50 mg/kg.                                  __________________________________________________________________________    N,N-dimethyl-3-[8-(methylthio)-dibenzo[b,f]-                                   thiepin-10-yl]-2-propynylamine maleate                                        (Product A)                >100                                              N,N,-dimethyl-3-(8-chloro-dibenzo[b,f]-                                        thiepin-10-yl)-2-propynylamine maleate                                        (Product B)                100                                               N,N-dimethyl-3-(8-chloro-3-methoxy-dibenzo[b,f]-                               thiepin-10-yl)-2-propynylamine methane-                                       sulfonate (Product C)      >100                                              Chlorpromazine              6                                                 __________________________________________________________________________

The table demonstrates that no or, respectively, very weak catalepticeffect is produced by Substances A, B and C in comparison tochlorpromazine, which does demonstrate cataleptic effects.

The demonstrate the neuroleptic effect of the products of the invention,representative compounds are utilized in the following tests:

I. Determination of Homovanillinic Acid

Two hours prior to being killed, rats are injected with the testsubstance.

Thereafter, the homovanillinic acid is extracted from the supernatantportion of a homogenized mixture of brains of the treated rats intobutylacetate and later into an aqueous solution and is oxidized withpotassium ferric cyanide to a fluorescent dimer. From an increasedconcentration of homovanillinic acid, (HVA). it can be demonstrated thatthe test substance words that same as chlorpromazine, that is, itincreases the turnover of dopamine in the basal ganglions. Thehomovanillinic titer in untreated rats is arbitrarily set at 100%.

A comparison between Substance A, B and C and chlorpromazine gave thefollowing results:

    __________________________________________________________________________    RESULTS:                                                                                             Dose    Increase of                                    Test Substance         mg/kg. p.o.                                                                           HVA %                                          __________________________________________________________________________    N,N-dimethyl-3-[8-(methylthio)-                                                dibenzo[b,f]thiepin-10-yl]-2-                                                 propynylamine maleate (Product A)                                                                   50      330                                            N,N-dimethyl-3-(8-chloro-dibenzo[b,f]-                                         thiepin-10-yl)-2-propynylamine maleate                                        (Product B)           50      370                                            N,N-dimethyl-3-(8-chloro-3-methoxy-                                            dibenzo[b,f]thiepin-10-yl)-2-                                                 propynylamine methanesulfonate                                                (Product C)           30      320                                            Chlorpromazine         20      321                                            __________________________________________________________________________

The compounds of the invention, i.e., the compounds of formulas I andIa, can be used in the form of pharmaceutical preparations, whichcontain them or their salts, in admixture with organic or inorganicpharmaceutically inert carriers suitable for enteral or parenteralapplication such as, for example, water, gelatin, milk sugar, starch,magnesium stearate, talc, vegetable oils, gum arabic,polyalkyleneglycols and the like. The pharmaceutical preparations can bein solid form, for example, tablets, dragees, suppositories, capsules orin liquid form, for example, as solution, suspensions, or emulsions. Thepreparation may be sterillized and/or contain additives such aspreservatives, stabilizers, wetting or emulsifying agents, or salts forvarying the osmotic pressure. The pharmaceutical preparations can alsocontain additional therapeutically active substances.

Preferably, the pharmaceutical dosage forms contain from about 1 toabout 200 mg. of a compound of formula I or Ia or an equivalent amountof its salts. Preferably, the oral dosage range is between about 0.1mg/kg/day to about 7.5 mg/kg/day. A preferable dosage range forparenteral preparations is in the range of from about 0.01 mg/kg/day toabout 0.75 mg/kg/day. It is understood, however, that theabove-mentioned ranges can be varied according to the individual needsand prescription of the practitioner.

As is evidnet, the compounds of formulas I and Ia and theirpharmaceutically acceptable acid addition have effects qualitativelysimilar to those of chlorpromazine, known for its therapeutic uses andproperties. Thus, the compounds of the invention demonstrate a patternof activity associated with neuroleptic agents of known efficacy andsafety.

The following examples further illustrate the invention. Alltemperatures are in degrees Centigrade, unless otherwise mentioned.

EXAMPLE 1 Preparation of N,N-dimethyl-3-(8-chloro-dibenzo [b,f]thiepin-10-yl)-2-propynylamine

63 G. of p-toluenesulfonic acid and 1,800 ml. of o-xylene are heated toboiling and the water present is distilled. The solution is reacted with90 g. of10-[3-(dimethylamino)-1-propynyl]-8-chloro-10,11-dihydro-dibenzo[b,f]thiepin-10-ol.The reaction mixture is maintained at the boiling temperature for 45minutes, whereby the remaining water is distilled. The mixture is cooledand poured into 90 ml. of 2N aqueous sodium hydroxide. The aqueous phaseis extracted with ether. The resulting organic phase is washed threetimes with water and subsequently extracted three times with aqueousmethanesulfonic acid. The aqueous phase is washed with water and madealkaline with concentrated sodium hydroxide. The reaction mixture isthen extracted with ether, and the ether extract washed with water,dried and evaporated, whereby there is obtainedN,N-dimethyl-3-(8-chloro-dibenzo[b,f,]thiepin-10-yl)-2-propylamine,which after recrystallization from hexane, has a melting point of118°-120° C. The maleate is precipitated from ethanol and melts at178°-1/2°.

The starting material10-[3-(dimethylamino)-1-propynyl]-8-chloro-10,11-dihydro-dibenzo[b,f,]thiepin-10-olcan be prepared as follows:

2100 Ml. of liquid ammonia is reacted with some crystalline ferricnitrate and subsequently with 10.4 g. of lithium metal over a 2-hourperiod. After stirring for 30 minutes, there are added 369 ml. ofdimethylamino-1-propyne over a 40-minute period, and the reactionmixture is stirred for an additional 45 minutes. Over a 105-minuteperiod, there is added dropwise a solution of 300 g. of8-chloro-10,11-dihydro-5H-dibenzo [b,f]thiepin-10-one in 1500 ml. oftetrahydrofuran. The reaction mixture is allowed to stand overnight. Thefollowing morning, the reaction mixture is treated with 228 g. ofammonium chloride in 600 ml. of water. The ammonia, thereafter, isevaporated. 900 Ml. of tetrahydrofuran are added, and the mixture isheated at reflux for 2 hours. The reaction mixture is evaporated,diluted with water and extracted with ether. The ether extract is washedwith water and extracted three times with aqueous methanesulfonic acid.The unreacted starting ketones can be recovered from the ethereal phase.The aqueous phase is made alkaline with concentrated sodium hydroxide,whereby there is obtained10-[3-(dimethylamino)-1-propynyl]-8-chloro-10,11-dihydrodibenzo[b,f,]thiepin-10-ol,which is taken up in chloroform. The chloroform phase is washed withwater, dried and evaporated, whereby there is obtained the above-namedproduct, which after recrystallization from acetone, has a melting pointof 150°-152°.

EXAMPLE 2

In a similar manner to that described in Example 1, from10-[3-(dimethylamino)-1-propynyl]-10,11-dihydro-8-(methylthio)-dibenzo[b,f]thiepin-10-ol,there is obtainedN,N-dimethyl-3-[8-(methylthio)-dibenzo[b,f]thiepin-10-yl]propynylamine.The maleate of the product has a melting point of 145°-146°.

The starting material can be prepared in an analogous manner to thatdescribed in Example 2, from 10-11-dihydro-8-(methylthio)-5H-dibenzo[b,f]thiepin-10-one and after recrystallization from benzene/hexane, hasa melting point of 142°-144°.

EXAMPLE 3

In a similar manner to that described in Example 1, from10-[3-(dimethylamino)-1-propynyl]-10,11-dihydro-8-methyl-dibenzo[b,f]thiepin-10-ol,there is obtainedN,N-dimethyl-3(8-methyl-dibenzo[b,f]thiepin-10-yl)-2-propynylamine. Thelatter compound can be purified by chromatography on silica gel withchloroform as the eluant solution. The corresponding maleate melts at121-123°.

The starting material can be prepared in an analogous manner to thatdescribed in Example 1, from 10-11-dihydro-8-methyl-5H-dibenzo[b,f]thiepin-10-one and melts after recrystallization from ether, at145°-147.5°.

EXAMPLE 4 Preparation of N,N-dimethyl-3-[8-chloro-dibenzo[b,f]-thiepin-10-yl]-2-propynylamine

A solution of 5.1 g. of 10-ethynyl-8-chloro-dibenzo [b,f]-thiepin in 40ml. of absolute dioxane is treated with 630 mg. of paraformaldehyde, 4.5ml. of a 6-M solution of dimethylamine in dioxane and 200 mg. of copper(II) acetate. The mixture is heated at 100° C. in a well-sealed flaskfor 2 hours. After cooling, the mixture is poured onto ice and thenacidified with 3-N methanesulfonic acid. The neutral products areremoved by extraction with ether. The aqueous phase is made alkalinewith ammonia. By extraction with ether, there is obtainedN,N-dimethyl-3-[8-chloro-dibenzo[b,f]thiepin-10-yl)]-2-propynylamine,which melts at 118°-120° C. after recrystallization from hexane. Themaleate melts at 178°-180° C.

In an analogous manner to that described above, the following compoundsare prepared:

N,n-dimethyl-3-[8-methylthio-dibenzo[b,f]thiepin-10-yl]-2-propynylamine;melting point 78°-80° C. The hydrochloride salt melts at 182°-184° C;

N,n-dimethyl-3-[8-methyl-dibenzo[b,f]thiepin-10-yl]-2-propynylamine;melting point 70°-72° C. The hydrochloride salt melts at 214°-216° C.

N,n-dimethyl-3-[8-fluoro-dibenzo[b,f]thiepin-10-yl]-2-propynylamine;melting point 59°-61° C. The hydrochloride salt melts at 234°-236° C;

N,n-diethyl-3-[8-chloro-dibenzo[b,f]thiepin-10-yl]-2-propynylamine. Themaleate salt melts at 146°-148° C;

N,n-dimethyl-3-[8-chloro-2-methyl-dibenzo[b,f]thiepin-10-yl]-2-propynylamine;melting point 96°-97° C. The hydrochloride salt melts at 174°-176° C;

1-[3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propynyl]-piperidine;melting point 59°-61° C. The methanesulfonate salt melts at 179°-181° C;

4-[3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propynyl]-morpholine,melting point 109° C. The methanesulfonate salt melts at 164°-166° C;

1-[3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propynyl]-pyrrolidine;melting point 76°-77° C. The methanesulfonate salt melts at 152°-154° C;

N,n-dimethyl-3-[8-fluoro-2-methyl-dibenzo[b,f]thiepin-10-yl]-2-propynylamine;melting point 74°-76° C. The hydrochloride salt melts at 231°-234° C;

N,n-dimethyl-3-[8-chloro-3-methoxy-dibenzo[b,f]thiepin-10-yl]-2-propynylamine;melting point 102°-104° C. The methanesulfonate salt melts at 211°-214°C;

N,n-dimethyl-3-[8-methoxy-dibenzo[b,f]thiepin-10-yl]-2-propynylamine;melting point 68°-71° C. The methanesulfonate salt melts at 132°-135° C;

N,n-dimethyl-3-[8-chloro-dibenzo[b,f]oxepin-10-yl]-2-propynylamine;melting point 62°-64° C. The methanesulfonate salt melts at 127°-129° C;

N,n-dimethyl-3-[8-isopropyl-dibenzo[b,f]thiepin-10-yl]-2-propynylamine;boiling point 170° C/0.02 mm Hg. The hydrochloride salt melts at194°-197° C;

N,n-dimethyl-3-[2,8-dichloro-dibenzo[b,f]thiepin-10-yl]-2-propynylamine;melting point 83°-85° C. The hydrochloride salt melts at 224°-227° C;

2-{[3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propynyl]-methylamine}-ethanol;melting point 87°-90° C. The maleate salt melts at 149°-151° C;

2-{4-[3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propynyl]-1-piperazinyl}ethanol;melting point 111°-113° C. The dihydrochloride salt melts at 253°-257°C;

N,n-dimethyl-3-[2-chloro-8-methylthio-dibenzo[b,f]thiepin-10-yl]-2-propynylamine;melting point 100°-103° C. The hydrochloride salt melts at 206°-208° C;

N,n-dimethyl-3-[2-methyl-8-methylthio-dibenzo[b,f]thiepin-10-yl]-2-propynylamine;melting point 80°-82° C. The hydrochloride salt melts at 185°-187° C;

N,n-dimethyl-3-[8-nitro-dibenzo[b,f]thiepin-10-yl]-2-propynylamine;melting point 113 -115° C. The maleate salt melts at 179°-182° C;

N,n-dimethyl-3-[8-chloro-11-methyl-dibenzo[b,f]thiepin-10-yl]-2-propynylamine;boiling point 210° C/0.2 mm Hg. The hydrochloride salt melts at240°-243° C;

N,n-3-[3-methyl-8-methylthio-dibenzo[b,f]thiepin-10-yl]-2-propynylamine;melting point 69°-72° C. The maleate salt melts at 161°-163° C;

N,n-dimethyl-3-[8-amino-dibenzo[b,f]thiepin-10-yl]-2-propynylamine;

N,n-dimethyl-3-[8-dimethylamino-dibenzo[b,f]thiepin-10-yl]-2-propynylamine;

N,n-dimethyl-3-[8-methylfulfonyl-dibenzo[b,f]thiepin-10-yl]-2-propynylamine;melting point 131°-133° C. The hydrochloride salt melts at 247°-250° C;

N,n-dimethyl-3-[8-dimethylsulfamoyl-dibenzo[b,f]thiepin-10-yl]-2-propynylamine;melting point 112°-114° C. The hydrochloride salts melts at 217°-220° C;

N,n-dimethyl-3-[8-trifluoromethyl-dibenzo[b,f]thiepin-10-yl]-2-propynylamine;melting point 88°-91° C. The hydrochloride salt melts at 196°-198° C.

The 10-ethynyl-8-chloro-dibenzo[b,f]thiepin used as the startingmaterial for the preparation ofN,N-dimethyl-3-(8-chloro-dibenzo[b,f]thiepin-10-yl]-2-propynylamine canbe prepared as follows:

56 G. of a trimethylethynylsilane/tetrahydrofuran mixture (correspondingto 0.44 mole of trimethylethynylsilane) in 300 ml. of benzene are slowlytreated dropwise at 0° C. with 235 ml. of n-butyllithium solution inhexane (corresponding to 0.4 mole). After stirring for an additional 0.5hour at this temperature, a solution of 52.8 g. of8-chloro-10,11-dihydro-5H-dibenzo[b,f]thiepin-10-one in 250 ml. ofbenzene is slowly added dropwise. The solution is left overnight in arefrigerator. On the following morning, the mixture is poured onto asolution comprising 250 g. of ammonia chloride in 1.5 liters of water.By extraction with benzene, there is obtained a mixture of unreactedstarting ketone [i.e.,8-chloro-10,11-dihydro-5H-dibenzo[b,f]thiepin-10-one]and8-chloro-10,11-dihydro-10-(trimethylsilylethynyl)-dibenzo[b,f]thiepin-10-olwhich is subjected directly to a water-cleavage step.

For this purpose, the mixture is taken up in 500 ml. of benzene and,after the addition of 1.2 g. of p-toluenesulfonic acid, boiled for 2hours at reflux, the resulting water is removed by distillation. Bydilution with benzene and washing to neutrality with water, there isobtained a mixture of unreacted starting ketone and[(8-chloro-dibenzo[b,f]thiepin-10-yl)-ethynyl]-trimethylsilane which istreated to cleave the trimethylsilyl group.

To the latter mixture, which has been dissolved in 660 ml. ofacetone/water (10:1 ), there is added dropwise over a period of 30minutes a solution of 64 g. of silver nitrate in 150 ml. of water, andthe mixture is stirred for an additional 1 hour. Then, a solution of 120g. of potassium cyanide in 500 ml. of water and 500 ml of benzene isadded and the mixture stirred until two clear phases result. Byextraction with benzene, there is obtained a mixture of unreactedstarting ketone and 10-ethynyl-8-chloro-dibenzo[b,f]thiepin which isseparated by chromatography on silica gel. The10-ethynyl-8-chloro-dibenzo[b,f]thiepin melts at 105°-108° C. afterrecrystallization from ether/n-pentane.

In an analogous manner to that described above, the following startingmaterials are prepared:

10-ethynyl-8-methylthio-dibenzo[b,f]thiepin; melting point 99°-101° C;

10-ethynyl-8-methyl-dibenzo[b,f]thiepin; melting point 94°-96° C;

10-ethynyl-8-fluoro-dibenzo[b,f]thiepin; oil (pure according tothin-layer chromatography);

10-ethynyl-8-chloro-2-methyl-dibenzo[b,f]thiepin; melting point127°-129° C;

10-ethynyl-8-fluoro-2-methyl-dibenzo[b,f]thiepin; melting point 74°-76°C;

10-ethynyl-8-chloro-3-methoxy-dibenzo[b,f]thiepin; melting point103°-105° C;

10-ethynyl-8-methoxy-dibenzo[b,f]thiepin; melting point 131°-136° C;

10-ethynyl-8-chloro-dibenzo[b,f]oxepin; melting point 118°-120° C;

10-ethynyl-8-isopropyl-dibenzo[b,f]thiepin; oil (pure according tothinlayer chromatography);

10-ethynyl-2,8-dichloro-dibenzo[b,f]oxepin; melting point 134°-137° C;

10-ethynyl-2-chloro-8-methylthio-dibenzo[b,f]thiepin; melting point100°-103° C; 10-ethyl-2-methyl-8-methylthio-dibenzo[b,f]thiepin; meltingpoint 124°-126° C;

10-ethynyl-8-nitro-dibenzo[b,f]thiepin; melting point 175-177° C;

10-ethynyl-8-chloro-11-methyl-dibenzo[b,f]thiepin; oil (pure accordingto thin-layer chromatography);

10-ethynyl-3-methyl-8-methylthio-dibenzo[b,f]thiepin; oil (pureaccording to thin-layer chromatography);

10-ethynyl-8-methylsulfonyl-dibenzo[b,f]thiepin; melting point 140-143°C; 10-ethynyl-8-amino-dibenzo[b,f]thiepin;

10-ethynyl-8-dimethylamino-dibenzo[b,f]thiepin;

10-ethynyl-8-dimethylsulfamoyl-dibenzo[b,f]thiepin; melting point133°-135° C; and

10-ethynyl-8-trifluoromethyl-dibenzo[b,f]thiepin; melting point 63-65°C.

EXAMPLE 5 Preparation ofN-methyl-3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propy-nylamine

A mixture of 20 ml. of dimethylformamide and 10 ml. of methylamine isslowly treated dropwise at about 0° C. with a solution of 4.7 g. of3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propynyl-1-ol mesylate in 30ml. of dimethylformamide. After about 1 hour, the mixture is poured ontowater. By extraction with ether, there is obtainedN-methyl-3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propynylamine whichmelts at 92-94° C. after recrystallization from ether. The maleate saltmelts at 104°-106° C.

In an analogous manner to that described above, the following compoundis prepared:

3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propynlamine; melting point ofthe maleate salt is 170°-172° C.

The 3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propyn-1-ol mesylate usedas the starting material for the preparation ofN-methyl-3-(8-chloro-dibenzo[b,f]-thiepin-10-yl)-2-propynylamine can beprepared as follows:

A solution of 13.5 g. of 10-ethynyl-8-dibenzo[b,f]thiepin in 150 ml. ofabsolute tetrahydrofuran is treated dropwise at room temperature with 52ml. of a 1-M solution of ethylmagnesium bromide solution intetrahydrofuran. After stirring the mixture for an additional hour, 1.85g. of paraformaldehyde are pyrrolyzed and led through the mixture ingaseous form. The solution, having now warmed to about 50° C., isstirred for an additional 30 minutes and then poured onto a saturated,aqueous ammonium chloride solution. By extraction with benzene andsubsequent chromatography on silica gel using benzene/methanol (20:1) asthe eluent, there is obtained3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propyn-1-ol which melts at111°-113° C. after recrystallization from ethyl acetate/petroleum ether.

A solution of 6 g. of3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propyn-1-ol in 50 ml. ofpyridine is treated dropwise at -10° C. to 0° C. with 1.7 ml. ofmethanesulfonyl chloride in 10 ml. of pyridine and stirred at thistemperature for 2 hours. After pouring onto ice, acidification withhydrochloric acid and extraction with eher, there is obtained3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propyn-1-ol mesylate whichmelts at 100°-102° C. after recrystallization from ether.

EXAMPLE 6 Preparation of2-{[3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2propynyl]-methylamino}-ethanol

A solution of 2 ml. of ethylene oxide in 10 ml. of ethanol is treatedwith a solution of 0.6 g. ofN-methyl-3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propynylamine in 5 ml.of ethanol and stirred at room temperature for about 4 hours. Thesolvent is evaporated and the residue partitioned between water andether. The ethereal phase is washed with a dilute aqueous ammoniasolution, dried over sodium sulfate and evaporated, whereby there isobtained2-{[3-(8-chloro-dibenzo[b,f]thiepin-10yl)-2-propynyl]-methylamino}-ethanolwhich melts at 86-88° C. after recrystallization from ether/n-pentane.

EXAMPLE 7 Preparation of 2-{4-[3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propynyl]-1-piperazinyl {-ethyl acetate

A solution of 5.0 g. of2-{4-[3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propynyl]-1-piperazinyl{-ethanol in 50 ml. of acetic anhydride is heated for 15 minutes on asteam-bath. After evaporation of the excess acetic anhydride undergreatly reduced pressure, the resulting oil is taken up in ether andwashed with saturated sodium bicarbonate solution. By concentration ofthe ethereal phase, there is obtained2-{4-[3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propynyl]-1-piperazinyl{-ethylacetate which melts at 96°-99° C. after recrystallization from ethylacetate/hexane.

In an analogous manner to that described above, there is obtained2-{[3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propynyl]-methylamino{-ethyl acetate which meltsat 48°-51° C. after recrystallization from petroleum ether.

EXAMPLE 8 Preparation of N,N-dimethyl-3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propynylamine N-oxide

A solution of 2 g. of N,N-dimethyl-3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propynylamine in 100 ml. of chloroform is treatedat -50° C. with 1.2 g. of mchloroperbenzoic acid. The solution isstirred for 15 minutes at this temperature, warmed to room temperatureand chromatographed on basic aluminum oxide using chloroform/methanol(9:1) as the eluant, whereby there is obtainedN,N-dimethyl-3-(8-chloro-dibenzo [b,f]thiepin-10-yl)-2-propynylamineN-oxide, which melts at 68°-69° C. after recrystallization from ethylacetate/petroleum ether.

The following Examples illustrate pharmaceutical preparations containingthe tricyclic compounds provided by the invention:

EXAMPLE 9

Tablets of the following composition are prepared:

                                      Example 9                                   __________________________________________________________________________    Tablets of the following composition are prepared:                                                        Per Tablet                                        __________________________________________________________________________    N,N-dimethyl-3-[8-(methylthio)-dibenzo-                                        [b,f]thiepin-10-yl]-2-propynylamine maleate                                                              25.00 g.                                          Lactose                     110.00 g.                                         Maize Starch                61.00 g.                                          Talc                        3.40 g.                                           Magnesium Stearate          0.60 g.                                                                       200.00 g.                                         __________________________________________________________________________

The ingredients are mixed together and tablets of 200 mg. each arepressed. Thereafter, if desired, the tablets can be coated withethylcellulose and Carbowax.

EXAMPLE 10

                  Example 10                                                      ______________________________________                                        Tablets of the following composition are prepared:                                                   Per Tablet                                             ______________________________________                                        N,N-dimethyl-3-[8-(methylthio)-dibenzo-                                        [b,f]thiepin-10-yl]-2-propynylamine                                                                   100.0 g.                                             Lactose                  202.0 g.                                             Maize Starch             80.0 g.                                              Hydrolyzed maize starch  20.0 g.                                              Calcium stearate         8.0 g.                                                                        410.0 g.                                             ______________________________________                                    

The active ingredient, lactose, maize starch and hydrolyzed maize starchare mixed together and granulated with water to a viscous paste. Thispaste is passed through a sieve and subsequently dried overnight at 45°C. Thereafter, the dried granulate is passed through a sieve and mixedwith the calcium stearate. The mixture obtained is pressed to tabletsweighing 410 mg. and having a diameter of about 10 mm.

EXAMPLE 11

                  Example 11                                                      ______________________________________                                        Tablets of the following composition are prepared:                                                Per Tablet                                                ______________________________________                                        N,N-dimethyl-3-[8-(methylthio)-dibenzo-                                        [b,f]thiepin-10-yl]-2-propynylamine                                                                   25.0 g.                                              Lactose                  114.0 g.                                             Maize Starch             50.0 g.                                              Gelatinized maize starch 8.0 g.                                               Calcium stearate         3.0 g.                                                                        200.0 g.                                             ______________________________________                                    

The active ingredient, lactose, maize starch and gelatinized maizestarch are intimately mixed with one another. The mixture is passedthrough a comminuting machine and subsequently moistened with water togive a thick paste. The moist mass is passed through a sieve, and theresulting moist granulate is dried at 45° C. The dried granulate ismixed thoroughly with the calcium stearate, and thereafter, pressed totablets weighing 200 mg. and having a diameter of about 8 mm.

EXAMPLE 12

                                      Example 12                                  __________________________________________________________________________    Tablets of the following composition are prepared:                                                        Per Tablet                                        __________________________________________________________________________    N,N-dimethyl-3-[8-(methylthio)-dibenzo-                                        [b,f]thiepin-10-yl]-2-propynylamine maleate                                                              14.5 g.                                           Lactose                     124.5 g.                                          Maize Starch                50.0 g.                                           Gelatinized maize starch    8.0 g.                                            Calcium stearate            3.0 g.                                                                        200.0 g.                                          __________________________________________________________________________

The active ingredient, lactose, maize starch and gelatinized maizestarch are intimately mixed with one another. The mixture is passedthrough a comminuting machine and subsequently moistened with water togive a thick paste. The moist mass is passed through a sieve, and theresulting moist granulate is dried at 45° C. The dried granulate ismixed thoroughly with the calcium stearate, and thereafter, pressed totablets weighing 200 mg. and having a diameter of about 8 mm.

EXAMPLE 13

                                      Example 13                                  __________________________________________________________________________    Capsules of the following composition are prepared:                                                      Per Capsule                                        __________________________________________________________________________    N,N-dimethyl-3-[8-(methylthio)-dibenzo-                                        [b,f]thiepin-10-yl]-2-propynylamine maleate                                                             29.0 g.                                            Lactose                    156.0 g.                                           Maize Starch               30.0 g.                                            Talc                       5.0 g.                                                                        220.0 g.                                           __________________________________________________________________________

The active ingredient, lactose and maize starch are mixed intimatelywith one another and passed through a comminuting machine. The mixtureis now mixed thoroughly with the talc and filled into hard gelatincapsules.

EXAMPLE 14

                  Example 14                                                      ______________________________________                                        Capsules of the following composition are prepared:                                                 Per Capsule                                             ______________________________________                                        N,N-dimethyl-3-[8-(methylthio)-dibenzo-                                        [b,f]thiepin-10-yl]-2-propynylamine                                                                  25.5 g.                                               Lactose                 159.5 g.                                              Maize Starch            30.0 g.                                               Talc                    5.0 g.                                                                        220.0 g.                                              ______________________________________                                    

The active ingredient, lactose and maize starch are mixed intimatelywith one another and passed through a comminuting machine. The mixtureis now mixed thoroughly with the talc and filled into hard gelatincapsules.

EXAMPLE 15

                  Example 15                                                      ______________________________________                                        A parenteral preparation of the following composition is prepared:            Each 1 ml. ampule contains:                                                   N,N-dimethyl-3-[8-(methylthio)-dibenzo-                                        [b,f]thiepin-10-yl]-2-propynylamine                                                                   10.20 mg.                                                                     (2% excess)                                          Methanesulfonic acid for injection                                                                     2.22 mg.                                             Glucose for injection    40.0 mg.                                             Water for injection q.s. ad                                                                            1.0 ml.                                              ______________________________________                                    

22.2 G. of methanesulfonic acid for injection, 102 g. of activeingredient and 400 g. of glucose are successively dissolved in a glassvessel in 8000 ml. of water for injection with stirring at roomtemperature.

Subsequently, water for injection is added to a total volume of 10,000ml. The solution is either aseptically filtered, filled into colorlessampules, gassed with nitrogen and sealed, or filled into colorlessampules, gassed with nitrogen, sealed and subsequently sterilized in acurrent of steam or autoclaved at 120° C. for 30 minutes.

Instead of the active ingredients used in Examples 9-15, there can, ofcourse, also be used in the preparations described therein, otherdibenzo[b,f]-thiepin derivatives of the present invention, for example:

N,n-dimethyl-3-(8-chloro-3-methoxy-dibenzo[b,f]thiepin-10-yl)-2-propynylamineor its methanesulfonate salt;

N,n-dimethyl-3-(8-chloro-dibenzo [b,f]thiepin-10-yl)-2-propynylamine orits maleate or methanesulfonate salt. Exemplary end products encompassedby claim 1 are also, for example, the following:

the compounds corresponding to the end products of Examples 1-8 and tothe above compounds which are methyl substituted in 11-position;

the compounds corresponding to the foregoing which are N-methyl,N,N-diethyl, N,N-dihydroxyethyl amines or N'-methylpiperazines insteadof N,N-dimethylamines; and

the N-oxides of the aforegoing compounds.

We claim:
 1. A compound of the formula ##STR12##wherein X is oxygen orsulfur; R₁ and R₂, independently, are hydrogen or lower alkyl; R₃ ishydrogen; R₆ is lower alkyl, lower alkyl-sulfonyl, hydroxy, loweralkoxy, lower alkylthio, di-(lower alkyl)-sulfamoyl, halogen,trifluoromethyl, nitro, amino or di-(lower alkyl)-amino; and R₇ and R₈,independently, are hydrogen, lower alkyl-sulfonyl, hydroxy, lower alkyl,lower alkoxy, lower alkylthio, di-(lower alkyl)-sulfamoyl, halogen,trifluoromethyl, nitro, amino or di-(lower alkyl)-amino.
 2. A compoundin accordance with claim 1,10-ethynyl-8-trifluoromethyl-dibenzo[b,f]thiepin.